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Abstract Background A strategy for reducing mental illness-related stigma in health-profession students is to include contact-based sessions in their educational curricula. In such sessions students are able to interact socially with a person that has a mental illness. We sought to evaluate the effectiveness of this strategy in a multi-centre study of pharmacy students. Methods The study was a randomized controlled trial conducted at three sites. Because it was necessary that all students receive the contact-based sessions, the students were randomized either to an early or late intervention, with the late intervention group not having participated in the contact-based education at the time when the primary outcome was assessed. The primary outcome, stigma, was assessed using an attitudes scale called the Opening Minds Survey for Health Care Providers (OMS-HC). Results We initially confirmed that outcomes were homogeneous across study centres, centre by group interaction, p = 0.76. The results were pooled across the three study centres. A significant reduction in stigma was observed in association with the contact-based sessions (mean change 4.3 versus 1.5, t=2.1, p=0.04). The effect size (Cohen’s d) was 0.45. A similar reduction was seen in the control group when they later received the intervention. Conclusions Contact-based education is an effective method of reducing stigma during pharmacy education. These results add to a growing literature confirming the effectiveness of contact-based strategies for stigma reduction in health profession trainees.

Abstract Background The role of exogenous hormone exposures in the development of meningioma is unclear, but these exposures have been proposed as one hypothesis to explain the over-abundance of such tumors in women. Methods The association between oral contraception (OC) or hormone replacement therapy (HRT) and intracranial meningioma in women was investigated using a population-based, matched case-control study. Exposures for 143 cases and 286 controls matched on age within five years were obtained by interview. Diagnoses were confirmed histopathologically and estrogen and progesterone receptor assays conducted. Results Although risk of meningioma appeared modestly elevated in past OC users (OR = 1.5, 95% CI 0.8 – 2.7), and in current users (OR = 2.5, 95% CI 0.5 – 12.6), the confidence intervals were wide. No significant association between meningioma risk and duration of OC use was found. Likewise, risk of meningioma was only weakly associated with past use of HRT (OR = 0.7, 95% CI 0.4 – 1.3), and not at all with current use of HRT (OR = 1.0, 95% CI 0.5 – 2.2). Of 142 available specimens, 2 (1%) expressed estrogen receptors, whereas 130 (92%) expressed progesterone receptors (PR). OC use was associated with increased risk of a meningioma expressing less rather than more PR (OR = 3.2, 95% CI 1.3 – 8.0). Overall, in post menopausal women, HRT use appeared to confer a non-significant protective effect, and was not associated with low or high PR expressing meningiomas. Conclusion This study found little evidence of associations between meningioma and exogenous hormone exposures in women but did suggest that some hormonal exposures may influence tumor biology in those women who develop meningioma.

Ruthenium(II) polypyridyl complexes (RPCs) that emit from triplet metal-to-ligand charge transfer (MLCT) states find a wide variety of uses ranging from luminophores to potential anti-cancer or anti-bacterial therapeutics. Herein we describe a greener, microwave-assisted synthetic pathway for the preparation of homoleptic [Ru(N^N) 3 ] 2+ and bis-heteroleptic [Ru(N^N) 2 (N'^N')] 2+ type complexes. This employs the bio-renewable solvent Cyrene™, dihydrolevoglucosenone, as a green alternative to N , N '-dimethylformamide (DMF) in the synthesis of Ru(N^N) 2 Cl 2 intermediate complexes, obtaining comparable yields for N^N = 2,2'-bipyridine, 1,10-phenanthroline and methylated derivatives. Employing these intermediates, a range of RPCs were prepared and we verify that the ubiquitous luminophore [Ru(bpy) 3 ] 2+ (bpy = 2,2'-bipyridine) can be prepared by this two-step green pathway where it is virtually indistinguishable from a commercial reference. Furthermore, the novel complexes [Ru(bpy) 2 (10,11-dmdppz)] 2+ (10,11-dmdppz = 10,11-dimethyl-dipyridophenazine) and [Ru(5,5'-dmbpy) 2 (10,11-dmdppz)] 2+ (5,5'-dmbpy = 5,5'-dimethyl-bpy) intercalate duplex DNA with high affinity (DNA binding constants, K b = 5.7 × 10 7 and 1.0 × 10 7 M -1 , respectively) and function as plasma membrane and nuclear DNA dyes for confocal and STED microscopies courtesy of their long-lived MLCT luminescence.

Non-culture based surveys show that the bacterial family Orbaceae is widespread in guts of insects, including wild Drosophila . Relatively few isolates have been described, and none has been described from Drosophila . We present the isolation and characterization of five strains of Orbaceae from wild-caught flies of the genera Drosophila (Diptera: Drosophilidae) and Neogriphoneura (Diptera: Lauxaniidae). Cells are generally rod-shaped, mesophilic, and measure 0.8-2.0 µm long by 0.3-0.5 µm wide. Optimal growth was observed under ambient atmosphere. Reconstruction of phylogenies from the 16S rRNA gene and from single-copy orthologs verify placement of these strains within Orbaceae . Cells exhibited similar fatty acid profiles to those of other Orbaceae . Strain lpD01 T shared 74% average nucleotide identity (ANI) with its closest relatives Ca. Schmidhempelia bombi Bimp and Zophobihabitans entericus IPMB12 T . Results from multiple genome-wide similarity comparisons indicate lpD01 T should be classified as a novel species within a novel genus. The major respiratory quinone for lpD01 T is ubiquinone Q-8. lpD02 T , lpD03, lpD04 T , and BiB T are more closely related to Orbus hercynius CN3 T (76, 77, 76, and 77% ANI, respectively) than to other described Orbaceae . Genomic and phylogenetic analyses suggest that lpD03 and lpD04 T belong to the same species and that lpD02 T , lpD03/lpD04 T , and BiB T are each novel species of the genus Orbus . The proposed names of these strains are Utexia brackfieldae gen. nov., sp. nov. (type strain lpD01 T =NCIMB 15517 T =ATCC TSD-399 T ), Orbus sturtevantii sp. nov (type strain lpD02 T =NCIMB 15518 T =ATCC TSD-400 T ), Orbus wheelerorum sp. nov. (type strain lpD04 T =NCIMB 15520 T =ATCC TSD-401 T ), and Orbus mooreae sp. nov (type strain BiB T =NCIMB 15516 T =ATCC TSD-402 T ). The isolation and characterization of these strains expands the repertoire of culturable bacteria naturally associated with insects, including the model organism D. melanogaster .

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multifaceted disease that affects millions globally. Despite its significant impact, the disease's etiology remains poorly understood, and symptom heterogeneity poses challenges for diagnosis and treatment. Joint hypermobility, commonly seen in hypermobile Ehlers-Danlos Syndrome (hEDS), has been observed in ME/CFS patients but its prevalence and clinical significance within this population are not well-characterized., Objective: To compare the characteristics of ME/CFS patients with and without joint hypermobility (JH+ and JH-) as assessed using the Beighton scoring system, and to explore whether JH+ ME/CFS patients exhibit distinct disease characteristics, comorbidities, and health-related quality of life (HRQOL)., Methods: The study used cross-sectional, self-reported data from 815 participants of the You + ME Registry. Participants were categorized as JH+ or JH- based on self-assessed Beighton scores and compared across demographics, comorbidities, family history, and symptoms. HRQOL was assessed using the Short Form-36 RAND survey and Karnofsky Performance Status., Results: 15.5% ( N = 126) of participants were classified as JH+. JH+ participants were more likely to be female, report Ehlers-Danlos Syndrome (EDS), Postural Orthostatic Tachycardia Syndrome (POTS), and a family history of EDS. They experienced worse HRQOL, particularly in physical functioning and pain, and a higher number of autonomic, neurocognitive, headache, gut, and musculoskeletal symptoms. Sensitivity analysis suggested that ME/CFS with concurrent JH+ and EDS was associated with more severe symptoms and greater functional impairment., Conclusion: ME/CFS patients with joint hypermobility, particularly those with EDS, demonstrate distinct clinical characteristics, including more severe symptomatology and reduced HRQOL. These findings highlight the need for comprehensive clinical assessments of ME/CFS patients with joint hypermobility. Understanding these relationships could aid in subgroup identification, improving diagnosis, and informing targeted therapeutic approaches. Further research is warranted to explore these associations and their implications for clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mudie, Ramiller, Whittaker and Phillips.)

Background: The COVID-19 pandemic created unprecedented challenges for the film industry. Following a shutdown of productions, The Safe Way Forward document was developed to outline disease mitigation protocols. Despite this framework, many unanticipated scenarios arose during reopening of film production with the ongoing pandemic., Aims: To identify and document promising practices for mitigating COVID-19 transmission in the film industry that can inform future pandemics and other industries., Methods: We conducted a literature search to review research regarding COVID-19 disease mitigation efforts in the film industry. Through client-facing consultancy and consultant group meetings, we identified those factors most important for disease mitigation in the film industry and applicable to future pandemics and other industries. The Delphi Method enabled experts to review lessons learned as studio consultants during the COVID-19 pandemic; learnings were coded and analyzed for recurring themes., Results: We identified anxiety, mistrust, and poor communication as key contributors to decreased compliance with COVID-19 protocols. In response, our team demonstrated multi-specialty expertise, provided scientific explanations, and developed trust by listening empathetically and responding with clear, consistent messaging. These measures served to alleviate anxiety, improve compliance, and provide a safe return to production., Conclusions: This study demonstrates the ability and agility of multi-disciplinary experts acting in the absence of clear guidance to support a safe return to film production. Workplace anxiety and non-compliance can be alleviated through effective communication by trusted experts. Lessons learned by our consultancy group can help protect workers across diverse industries in future pandemics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The capability to reach ultracold atomic temperatures in compact instruments has recently been extended into space 1,2 . Ultracold temperatures amplify quantum effects, whereas free fall allows further cooling and longer interactions time with gravity-the final force without a quantum description. On Earth, these devices have produced macroscopic quantum phenomena such as Bose-Einstein condensates (BECs), superfluidity, and strongly interacting quantum gases 3 . Terrestrial quantum sensors interfering the superposition of two ultracold atomic isotopes have tested the universality of free fall (UFF), a core tenet of Einstein's classical gravitational theory, at the 10 -12 level 4 . In space, cooling the elements needed to explore the rich physics of strong interactions or perform quantum tests of the UFF has remained elusive. Here, using upgraded hardware of the multiuser Cold Atom Lab (CAL) instrument aboard the International Space Station (ISS), we report, to our knowledge, the first simultaneous production of a dual-species BEC in space (formed from 87 Rb and 41 K), observation of interspecies interactions, as well as the production of 39 K ultracold gases. Operating a single laser at a 'magic wavelength' at which Rabi rates of simultaneously applied Bragg pulses are equal, we have further achieved the first spaceborne demonstration of simultaneous atom interferometry with two atomic species ( 87 Rb and 41 K). These results are an important step towards quantum tests of UFF in space and will allow scientists to investigate aspects of few-body physics, quantum chemistry and fundamental physics in new regimes without the perturbing asymmetry of gravity., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Toolkits of plasmids and genetic parts streamline the process of assembling DNA constructs and engineering microbes. Many of these kits were designed with specific industrial or laboratory microbes in mind. For researchers interested in non-model microbial systems, it is often unclear which tools and techniques will function in newly isolated strains. To address this challenge, we designed the Pathfinder toolkit for quickly determining the compatibility of a bacterium with different plasmid components. Pathfinder plasmids combine three different broad-host-range origins of replication with multiple antibiotic resistance cassettes and reporters, so that sets of parts can be rapidly screened through multiplex conjugation. We first tested these plasmids in Escherichia coli, a strain of Sodalis praecaptivus that colonizes insects, and a Rosenbergiella isolate from leafhoppers. Then, we used the Pathfinder plasmids to engineer previously unstudied bacteria from the family Orbaceae that were isolated from several fly species. Engineered Orbaceae strains were able to colonize Drosophila melanogaster and could be visualized in fly guts. Orbaceae are common and abundant in the guts of wild-caught flies but have not been included in laboratory studies of how the Drosophila microbiome affects fly health. Thus, this work provides foundational genetic tools for studying microbial ecology and host-associated microbes, including bacteria that are a key constituent of the gut microbiome of a model insect species., (© 2023. The Author(s).)

Background: Urinary tract infections (UTI) account for millions of office visits and approximately 400 000 hospital admissions every year in the United States; as a result, the cost burden of UTI in the USA is estimated at approximately $2.8 billion. There is a great deal of interest in finding newer, faster, and more reliable methods for diagnosing UTI as compared to the standard urine culture., Methods: An automated fluorescent microbial cell counter was used to compare urine samples found to be positive for Escherichia coli UTI via cell culturing (n = 11) with UTI-negative samples (n = 10)., Results: Patients with a positive urine culture had significantly higher cell count results using the microbial cell counter (1.01 × 10 8 cells/mL) as compared to the negative samples (2.35 × 10 6 cells/mL; P = .0022)., Conclusions: These observations suggest that automated microbial cell counters may serve as a rapid, objective method for the detection of bacteriuria in urine samples submitted for evaluation of suspected UTI., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals Inc.)

Home Care Aides (HCAs) have nearly four times the rate of injury as the general U.S. work force. In 2015, the Service Employees International Union 775 Benefits Group conducted a health and safety survey with 672 HCAs in Washington State. The goal was to identify the risk factors for injury and to better assess injury rates through self-report. Quantitative analyses assessed injury prevalence and barriers in reporting injury. Overall, 13 percent responded that they had ever had an injury that required medical attention while working as an HCA. These rates are significantly higher for HCAs employed by home care agencies compared with HCAs who work independently. Over a third reported moderate to high levels of hesitancy in reporting an on-the-job injury; these rates were even higher for independent providers. Study findings suggest that HCAs are well informed about appropriate next steps following workplace injury, but strong barriers may prevent them from attempting the reporting process.

Objective: To describe the natural history, antenatal and postnatal therapy, and clinical outcomes of Australian patients with fetomaternal/neonatal alloimmune thrombocytopenia (NAIT) recorded in the Australian NAIT registry., Methods: Analysis of registry data of Australian mothers treated antenatally for NAIT and any fetus/newborn with thrombocytopenia (TCP) and maternal human platelet antigen (HPA) antibodies., Results: Ninety four potential cases (91 pregnancies; three twin pregnancies) were registered between December 2004 and September 2015 with 76 confirmed or treated as NAIT. NAIT was frequently unanticipated (44 cases, 58%), whilst 32 cases (42%) were anticipated due to personal or family history. In 70/76 cases, the diagnosis of NAIT was made based on HPA antibody results; anti-HPA-1a was most commonly detected (58/70, 82%), followed by anti-HPA-5b (5/70, 7%). Intracranial haemorrhage (ICH) was detected in seven cases (9%). Maternal antenatal therapy resulted in improved clinical outcomes. For antenatally treated cases, whilst 10/29 (34%) neonates had severe TCP, only one ICH was detected., Conclusions: This study provides data on contemporary "real world" management of Australian mothers and babies with NAIT. Antenatal IVIG therapy was associated with better neonatal outcomes. Maternal side-effects and treatment costs were substantial.

Introduction: A rate-based understanding of home care aides' adverse occupational outcomes related to their work location and care tasks is lacking., Methods: Within a 30-month, dynamic cohort of 43 394 home care aides in Washington State, injury rates were calculated by aides' demographic and work characteristics. Injury narratives and focus groups provided contextual detail., Results: Injury rates were higher for home care aides categorized as female, white, 50 to <65 years old, less experienced, with a primary language of English, and working through an agency (versus individual providers). In addition to direct occupational hazards, variability in workload, income, and supervisory/social support is of concern., Conclusions: Policies should address the roles and training of home care aides, consumers, and managers/supervisors. Home care aides' improved access to often-existing resources to identify, manage, and eliminate occupational hazards is called for to prevent injuries and address concerns related to the vulnerability of this needed workforce., (© 2017 Wiley Periodicals, Inc.)

Lymphatic vessels are vital for the trafficking of immune cells from the interstitium to draining lymph nodes during inflammation. Hypertension is associated with renal infiltration of activated immune cells and inflammation; however, it is unknown how renal lymphatic vessels change in hypertension. We hypothesized that renal macrophage infiltration and inflammation would cause increased lymphatic vessel density in hypertensive rats. Spontaneously hypertensive rats (SHR) that exhibit hypertension and renal injury (SHR-A3 strain) had significantly increased renal lymphatic vessel density and macrophages at 40 wk of age compared with Wistar-Kyoto (WKY) controls. SHR rats that exhibit hypertension but minimal renal injury (SHR-B2 strain) had significantly less renal lymphatic vessel density compared with WKY rats. The signals for lymphangiogenesis, VEGF-C and its receptor VEGF-R3, and proinflammatory cytokine genes increased significantly in the kidneys of SHR-A3 rats but not in SHR-B2 rats. Fischer 344 rats exhibit normal blood pressure but develop renal injury as they age. Kidneys from 24-mo- and/or 20-mo-old Fischer rats had significantly increased lymphatic vessel density, macrophage infiltration, VEGF-C and VEGF-R3 expression, and proinflammatory cytokine gene expression compared with 4-mo-old controls. These data together demonstrate that renal immune cell infiltration and inflammation cause lymphangiogenesis in hypertension- and aging-associated renal injury., (Copyright © 2017 the American Physiological Society.)

Objectives: To evaluate the use of routinely collected data to determine the cause(s) of critical bleeding in patients who receive massive transfusion (MT)., Background: Routinely collected data are increasingly being used to describe and evaluate transfusion practice., Materials/methods: Chart reviews were undertaken on 10 randomly selected MT patients at 48 hospitals across Australia and New Zealand to determine the cause(s) of critical bleeding. Diagnosis-related group (DRG) and International Classification of Diseases (ICD) codes were extracted separately and used to assign each patient a cause of critical bleeding. These were compared against chart review using percentage agreement and kappa statistics., Results: A total of 427 MT patients were included with complete ICD and DRG data for 427 (100%) and 396 (93%), respectively. Good overall agreement was found between chart review and ICD codes (78·3%; κ = 0·74, 95% CI 0·70-0·79) and only fair overall agreement with DRG (51%; κ = 0·45, 95% CI 0·40-0·50). Both ICD and DRG were sensitive and accurate for classifying obstetric haemorrhage patients (98% sensitivity and κ > 0·94). However, compared with the ICD algorithm, DRGs were less sensitive and accurate in classifying bleeding as a result of gastrointestinal haemorrhage (74% vs 8%; κ = 0·75 vs 0·1), trauma (92% vs 62%; κ = 0·78 vs 0·67), cardiac (80% vs 57%; κ = 0·79 vs 0·60) and vascular surgery (64% vs 56%; κ = 0·69 vs 0·65)., Conclusion: Algorithms using ICD codes can determine the cause of critical bleeding in patients requiring MT with good to excellent agreement with clinical history. DRG are less suitable to determine critical bleeding causes., (© 2016 British Blood Transfusion Society.)

Background: The Australian and New Zealand (ANZ) Massive Transfusion (MT) Registry (MTR) has been established to improve the quality of care of patients with critical bleeding (CB) requiring MT (≥ 5 units red blood cells (RBC) over 4 h). The MTR is providing data to: (1) improve the evidence base for transfusion practice by systematically collecting data on transfusion practice and clinical outcomes; (2) monitor variations in practice and provide an opportunity for benchmarking, and feedback on practice/blood product use; (3) inform blood supply planning, inventory management and development of future clinical trials; and (4) measure and enhance translation of evidence into policy and patient blood management guidelines. The MTR commenced in 2011. At each participating site, all eligible patients aged ≥18 years with CB from any clinical context receiving MT are included using a waived consent model. Patient information and clinical coding, transfusion history, and laboratory test results are extracted for each patient's hospital admission at the episode level., Results: Thirty-two hospitals have enrolled and 3566 MT patients have been identified across Australia and New Zealand between 2011 and 2015. The majority of CB contexts are surgical, followed by trauma and gastrointestinal haemorrhage. Validation studies have verified that the definition of MT used in the registry correctly identifies 94 % of CB events, and that the median time of transfusion for the majority of fresh products is the 'product event issue time' from the hospital blood bank plus 20 min. Data linkage between the MTR and mortality databases in Australia and New Zealand will allow comparisons of risk-adjusted mortality estimates across different bleeding contexts, and between countries. Data extracts will be examined to determine if there are differences in patient outcomes according to transfusion practice. The ratios of blood components (e.g. FFP:RBC) used in different types of critical bleeding will also be investigated., Conclusions: The MTR is generating data with the potential to have an impact on management and policy decision-making in CB and MT and provide benchmarking and monitoring tools for immediate application.

Objectives: To characterize the leading causes of death for the urban American Indian/Alaska Native (AI/AN) population and compare with urban White and rural AI/AN populations., Methods: We linked Indian Health Service patient registration records with the National Death Index to reduce racial misclassification in death certificate data. We calculated age-adjusted urban AI/AN death rates for the period 1999-2009 and compared those with corresponding urban White and rural AI/AN death rates., Results: The top-5 leading causes of death among urban AI/AN persons were heart disease, cancer, unintentional injury, diabetes, and chronic liver disease and cirrhosis. Compared with urban White persons, urban AI/AN persons experienced significantly higher death rates for all top-5 leading causes. The largest disparities were for diabetes and chronic liver disease and cirrhosis. In general, urban and rural AI/AN persons had the same leading causes of death, although urban AI/AN persons had lower death rates for most conditions., Conclusions: Urban AI/AN persons experience significant disparities in death rates compared with their White counterparts. Public health and clinical interventions should target urban AI/AN persons to address behaviors and conditions contributing to health disparities.

Introduction: Multiple studies have demonstrated improved perinatal outcomes for group prenatal care (GPC) when compared to traditional prenatal care. Benefits of GPC include lower rates of prematurity and low birth weight, fewer cesarean deliveries, improved breastfeeding outcomes and improved maternal satisfaction with care. However, the outpatient financial costs of running a GPC program are not well established., Methods: This study involved the creation of a financial model that forecasted costs and revenues for prenatal care groups with various numbers of participants based on numerous variables, including patient population, payor mix, patient show rates, staffing mix, supply usage and overhead costs. The model was developed for use in an urban underserved practice., Results: Adjusted revenue per pregnancy in this model was found to be $989.93 for traditional care and $1080.69 for GPC. Cost neutrality for GPC was achieved when each group enrolled an average of 10.652 women with an enriched staffing model or 4.801 women when groups were staffed by a single nurse and single clinician., Conclusions: Mathematical cost-benefit modeling in an urban underserved practice demonstrated that GPC can be not only financially sustainable but possibly a net income generator for the outpatient clinic. Use of this model could offer maternity care practices an important tool for demonstrating the financial practicality of GPC.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening thrombotic microangiopathy (TMA). In 2009, the Australian TTP/TMA registry was established to collect data on patients presenting with TTP/TMA throughout Australia., Aim: To summarise information on the diagnosis and management of patients with TTP collected in the first 5 years (2009-2014) of the Australian TTP registry., Methods: Registry data from June 2009 to October 2014 were reviewed., Results: Fifty-seven patients were identified with TTP (defined as ADAMTS13 activity <10%), accounting for 72 clinical episodes. ADAMTS13 inhibitor testing was performed in nine out of 57 patients (16%), reflecting the limited availability of accredited testing facilities. Sixty-seven out of 72 episodes were treated with therapeutic plasma exchange (PEx) using cryodepleted plasma (40% of episodes), fresh frozen plasma (36%) or a mixture (22%). Median exposure to plasma products was 55.9 L. PEx was commenced ≥2 days from stated diagnosis in 15% of episodes. Adverse reactions to PEx were common with documented allergic reactions (including life threatening) in 21% of episodes. Adjunctive immunosuppression was documented in 76% of episodes (corticosteroid 71% and rituximab 39%). Platelet transfusion was administered in 15% of episodes., Conclusions: Data from the Australian TTP/TMA registry suggest a heterogenous approach to the diagnosis and management of TTP in Australia over the assessed period. These observations highlight areas for improvement and standardisation of practice, including comprehensive diagnostic testing, more immediate access to PEx and a more uniform approach to adjunctive immunosuppression and supportive care., (© 2015 Royal Australasian College of Physicians.)

Objective: To determine the relationship between depression and diabetes management among urban American Indians/Alaska Natives (AI/ANs)., Design: Retrospective, cross-sectional analysis of medical records., Setting: 33 Urban Indian Health Organizations that participated in the Indian Health Service Diabetes Care and Outcomes Audit., Patients: 3,741 AI/AN patient records., Main Outcome Measures: Diabetes management outcomes, including HbA1c, smoking, BMI, systolic blood pressure, creatinine, total cholesterol, and receipt of preventive services., Results: Individuals with depression and diabetes were 1.5 times more likely to smoke than individuals with diabetes but without depression (OR=1.51; 95% Cl: 1.23, 1.86), controlling for age, sex, and facility. After adjustment, the geometric mean BMI in diabetes patients with depression was 3% higher than in patients without depression (β=.034; 95% CI: .011, .057)., Conclusions: Urban AI/ANs with diabetes and depression are more likely to smoke and have higher BMI than those with diabetes but without depression. These findings inform programmatic efforts to address the care of patients with both depression and diabetes.

Background and Objectives: The type and clinical characteristics of patients identified with commonly used definitions of massive transfusion (MT) are largely unknown. The objective of this study was to define the clinical characteristics of patients meeting different definitions of MT for the purpose of patient recruitment in observational studies., Materials and Methods: Data were extracted on all patients who received red blood cell (RBC) transfusions in 2010 at three tertiary Australian hospitals. MT patients were identified according to three definitions: ≥10 units RBC in 24 h (10/24 h), ≥6 units RBC in 6 h (6/6 h) and ≥5 units RBC in 4 h (5/4 h). Clinical coding data were used to assign bleeding context. Data on in-hospital mortality were also extracted., Results: Five hundred and forty-two patients met at least one MT definition, with 236 (44%) included by all definitions. The most inclusive definition was 5/4 h (508 patients, 94%) followed by 6/6 h (455 patients, 84%) and 10/24 h (251 patients, 46%). Importantly, 40-55% of most types of critical bleeding events and 82% of all obstetric haemorrhage cases were excluded by the 10/24 h definition. Patients who met both the 5/4 h and 10/24 h definitions were transfused more RBCs (19 vs. 8 median total RBC units; P < 0·001), had longer ventilation time (120 vs. 55 h; P < 0·001), median ICU (149 vs. 99 h; P < 0·001) and hospital length of stay (23 vs. 18 h; P = 0·006) and had a higher in-hospital mortality rate (23·3% vs. 16·4%; P = 0·050)., Conclusion: The 5/4 h MT definition was the most inclusive, but combination with the 10/24 h definition appeared to identify a clinically important patient cohort., (© 2014 International Society of Blood Transfusion.)

Objectives: Evidence is accumulating of adverse outcomes associated with transfusion of blood components. If there are differences in perioperative transfusion rates in cardiac surgery, and what hospital factors may contribute, requires further investigation., Methods: Analysis of 42,743 adult patients who underwent 43,482 procedures from 2005 to 2011 at 25 Australian hospitals, according to the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database. Multiple logistic regression examined associations of patient and hospital characteristics with transfusion of ≥1 red blood cell (RBC) unit; platelet (PLT), fresh frozen plasma (FFP), and cryoprecipitate (CRYO) doses; and ≥5 RBC units, from surgery until hospital discharge., Results: Procedures included 24,222 (55%) isolated coronary artery bypass grafts, 7299 (17%) isolated valve, 4714 (11%) coronary artery bypass graft and valve, and 7247 (17%) other procedures. After adjustment for various patient and procedure characteristics, transfusion rates varied across hospitals for ≥1 RBC unit from 22% to 67%, ≥5 RBC units from 5% to 25%, ≥1 PLT dose from 11% to 39%, ≥1 FFP dose from 11% to 48% and ≥1 CRYO dose from 1% to 20%. Hospital characteristics, including state or territory, private versus public, and teaching versus nonteaching, were not associated with variation in transfusion rates., Conclusions: Variation in transfusion of all components and large volume RBC was identified, even after adjustment for patient and procedural factors known to influence transfusion, and this was not explained by hospital characteristics., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: To evaluate the outcomes following recombinant activated factor VII (rFVIIa) use during abdominal aortic aneurysms (AAA) repair., Design: AAA patients were selected from the Australian and New Zealand Haemostasis Registry (ANZHR) who received off-licence rFVIIa to control critical bleeding., Methods: Patient characteristics and outcomes were compared between responders (bleeding stopped/attenuated) and non-responders (bleeding continued) to rFVIIa, stratified by aneurysm status (ruptured (r-AAA) vs. non-ruptured (nr-AAA)). Patients were also scored using POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity) and Hardman Index mortality predictive models., Results: In total, 77 AAA patients were included in the analysis. Approximately 73% (n = 56) of them had ruptured aneurysms and about 50% (n = 35/70 with known data) responded positively to rFVIIa. Eleven incidents of thromboembolic adverse events were reported in 9 patients (6 r-AAA and 3 nr-AAA). Responders in both ruptured and non-ruptured groups had significantly lower 28-day mortality than non-responders (r-AAA: 40% (10/25) vs. 92% (24/26); P < 0.001; nr-AAA: 30% (3/10) vs. 67% (6/9); P < 0.01). Mortality predictive models did not show any difference between overall observed and expected mortality in ANZHR patients., Conclusion: Patients who responded to rFVIIa had a lower mortality than those who did not respond to the treatment., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Introduction: The Australian and New Zealand Haemostasis Registry (ANZHR) included patients who received off-licence recombinant activated factor VII (rFVIIa) for critical bleeding from 2000 to 2009. Approximately 1.3% of the ANZHR patients were Jehovah's Witnesses (JWs). We compared them with the non-JW patients in the registry., Methods: Patient characteristics (e.g. gender, context of bleeding), factors influencing rFVIIa use (e.g. body temperature and pH) and outcomes (e.g. bleeding response (stopped/attenuated or unchanged) to rFVIIa, mortality) were compared between JW and non-JW patients using Fisher's exact chi-square tests and Kruskal-Wallis tests., Results: A total of 42 JW and 3134 non-JW patients were included in the analysis. Approximately 99% (n = 3098) of non-JWs received blood products compared with only 30% (n = 13) of JWs (P < 0.01). The distribution of gender and contexts of critical bleeding in the two groups was significantly different. Approximately 17% of the non-JW patients were hypothermic (T < 35°C) and about 19% were acidotic (pH < 7.2) at the time of initial rFVIIa administration. Conversely, none of the JWs were hypothermic and only one was acidotic. The proportion of positive responders to rFVIIa (stopped/attenuated bleeding following rFVIIa use) was similar in both groups (75% non-JWs, 74% JWs; P = 1.0). Approximately 28% of non-JW and 17% of JW patients were deceased by day 28 following rFVIIa use (P = 0.16)., Discussion: Several factors were observed to be significantly different between JW and non-JW patients, yet the proportions of responders to rFVIIa were similar in both groups. The actual factors influencing response to rFVIIa are yet to be determined., (© 2012 The Authors. ANZ Journal of Surgery © 2012 Royal Australasian College of Surgeons.)

Background: Critically bleeding trauma patients require coordinated and efficient decision-making processes to ensure optimal management of their massive transfusion (MT) requirements. Human factors (HFs) is a discipline that investigates factors influencing work processes from the organizational, group, and individual levels. Given the complexity of trauma resuscitation, implementing any intervention for decision support in MT is challenging and may benefit from a HFs-assisted approach., Study Design and Methods: A systematic review was performed to identify reports of the introduction of any type of decision support for the provision of MT in critically bleeding adult trauma patients. Crucial contributions reported to influence design and uptake of the intervention were categorized into four HFs categories (environment, human, machine, and task). Extracted information was supplemented by surveying the contact authors. Evidence of clinical practice changes resulting from the intervention was also considered., Results: We identified nine studies that had reported an intervention implementing new practice guidelines or a MT protocol. All were before-and-after comparative cohort studies and used historical controls as the preintervention cohort., Conclusion: Based on the identified reports, this review provides a HFs-assisted approach to aid clinicians and policy makers with the implementation of decision support for MT in the trauma care setting., (© 2012 American Association of Blood Banks.)

Objective: To examine off-label recombinant factor VIIa (rFVIIa) use in pediatric patients including clinical indications, dose, adverse events, and outcomes., Methods: All pediatric patients entered into the Haemostasis Registry from 75 participating hospitals were analyzed., Results: Three hundred and eighty-eight pediatric patients received off-label rFVIIa from 2003 to 2009. Median age was 12 months (interquartile range 1 month to 11 years). Clinical context included cardiac surgery (52.1%), medical (11.6%), other surgery (10.8%), hematology/oncology (10.3%), trauma (9.3%), intracranial hemorrhage (3.1%), and liver disease (2.8%). Twenty-six patients received extracorporeal membrane oxygenation at the time of rFVIIa administration. Median first dose was 114 μg/kg (interquartile range 90-181; range 7-2250). Thirty-four percent received >1 dose. There was a reduction in usage of red blood cells, platelets, fresh-frozen plasma, and cryoprecipitate in the 24 hours after the first dose for all patients (all P values < .001). Thromboembolic adverse events (TEAs) were reported in 5.4%. No association between TEA and size of first dose was found. Where data were available, 82% of patients were subjectively classified as responding to rFVIIa. Overall 28-day mortality was 27%. In multivariate analysis, pH values before administration and clinical context were independently associated with response to first dose and 28-day mortality., Conclusions: There was a significant reduction in blood product administration after rFVIIa and a subjective response rate of 82%. Both pH and clinical context were associated with response to rFVIIa and mortality. Overall, 5.4% had a TEA reported.

The neuropathologic examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently used clinical diagnostic methods, clinical and neuropathologic data from the National Alzheimer's Coordinating Center, which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer Disease Centers (ADCs), were collected as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on "probable" and "possible" AD levels of clinical confidence and 4 levels of neuropathologic confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathologic criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathologic diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in subjects with dementia than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiologic studies.

Objective: At the time of licensing by regulatory agencies, the full range of risks and possible adverse drug reactions associated with a medication is rarely fully realized. This commentary aims to describe the role of registries as useful components of postmarketing pharmacovigilance systems for monitoring highly specialized medications associated with significant financial costs., Study Design and Setting: We consider the limitations of traditional pharmacovigilance programs and discuss the strengths, limitations, and uses of registries in postmarketing pharmacovigilance systems., Results: Registries have become increasingly appealing in postmarketing surveillance of medications; however, their exact role continues to evolve. Key registry projects, including the Prospective Immunogenicity Surveillance Registry, British Society for Rheumatology Biologics Register, Australian Rheumatology Association Database, the Haemostasis Registry, and the Bosentan Patient Registry highlight the value of registries for monitoring the incidence of rare adverse events., Conclusion: Although often limited by lack of a control group and the need for complete case ascertainment to maintain data integrity, registries are a useful component of postmarketing pharmacovigilance systems for monitoring highly specialized medications associated with significant financial costs., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: Assessing the reliability of clinical registries is important for ensuring the availability of credible data. Therefore, this study aimed to investigate the reliability of data collected by the Australian and New Zealand Haemostasis Registry (the registry)., Design: Data from 5% of randomly selected registry cases were re-abstracted by an independent data auditor who was blinded to the results of the original data abstraction. Categorical data were investigated for agreement between original and re-abstracted data. The mean difference and standard deviations (SD) of differences were calculated for continuous variables. We estimated a 'prediction interval' as the mean difference ± twice the SD of differences. We computed a coefficient of variation as the SD of differences., Setting: The registry records all cases of off-licence use of recombinant activated factor VII (rFVIIa) at participating institutions (on-licence use of rFVIIa is not recorded)., Results: Data on 76 registry cases (6% of registry) were re-abstracted. Various parameters demonstrated high levels of inter-rater reliability, including age, gender and intensive care unit admission (88, 99 and 99% agreement, respectively). Other variables were highly unreliable, including crystalloid infusion volumes (coefficient of variation 123.01%), red blood cell units (92.05%) and time from bleeding onset to administration of rFVIIa (153.06%)., Conclusions: Registry audits are useful for identifying variables with poor reliability. Repeated audits will not improve data reliability; however, they can assist in identifying and evaluating the impact of modified data collection processes on improving data reliability.

Background: Hospital transfusion laboratories collect information regarding blood transfusion and some registries gather clinical outcomes data without transfusion information, providing an opportunity to integrate these two sources to explore effects of transfusion on clinical outcomes. However, the use of laboratory information system (LIS) data for this purpose has not been validated previously., Study Design and Methods: Validation of LIS data against individual patient records was undertaken at two major centers. Data regarding all transfusion episodes were analyzed over seven 24-hour periods., Results: Data regarding 596 units were captured including 399 red blood cell (RBC), 95 platelet (PLT), 72 plasma, and 30 cryoprecipitate units. They were issued to: inpatient 221 (37.1%), intensive care 109 (18.3%), outpatient 95 (15.9%), operating theater 45 (7.6%), emergency department 27 (4.5%), and unrecorded 99 (16.6%). All products recorded by LIS as issued were documented as transfused to intended patients. Median time from issue to transfusion initiation could be calculated for 535 (89.8%) components: RBCs 16 minutes (95% confidence interval [CI], 15-18 min; interquartile range [IQR], 7-30 min), PLTs 20 minutes (95% CI, 15-22 min; IQR, 10-37 min), fresh-frozen plasma 33 minutes (95% CI, 14-83 min; IQR, 11-134 min), and cryoprecipitate 3 minutes (95% CI, -10 to 42 min; IQR, -15 to 116 min)., Conclusions: Across a range of blood component types and destinations comparison of LIS data with clinical records demonstrated concordance. The difference between LIS timing data and patient clinical records reflects expected time to transport, check, and prepare transfusion but does not affect the validity of linkage for most research purposes. Linkage of clinical registries with LIS data can therefore provide robust information regarding individual patient transfusion. This enables analysis of joint data sets to determine the impact of transfusion on clinical outcomes., (© 2010 American Association of Blood Banks.)

Introduction: In critically ill patients, it is uncertain whether exposure to older red blood cells (RBCs) may contribute to mortality. We therefore aimed to evaluate the association between the age of RBCs and outcome in a large unselected cohort of critically ill patients in Australia and New Zealand. We hypothesized that exposure to even a single unit of older RBCs may be associated with an increased risk of death., Methods: We conducted a prospective, multicenter observational study in 47 ICUs during a 5-week period between August 2008 and September 2008. We included 757 critically ill adult patients receiving at least one unit of RBCs. To test our hypothesis we compared hospital mortality according to quartiles of exposure to maximum age of RBCs without and with adjustment for possible confounding factors., Results: Compared with other quartiles (mean maximum red cell age 22.7 days; mortality 121/568 (21.3%)), patients treated with exposure to the lowest quartile of oldest RBCs (mean maximum red cell age 7.7 days; hospital mortality 25/189 (13.2%)) had an unadjusted absolute risk reduction in hospital mortality of 8.1% (95% confidence interval = 2.2 to 14.0%). After adjustment for Acute Physiology and Chronic Health Evaluation III score, other blood component transfusions, number of RBC transfusions, pretransfusion hemoglobin concentration, and cardiac surgery, the odds ratio for hospital mortality for patients exposed to the older three quartiles compared with the lowest quartile was 2.01 (95% confidence interval = 1.07 to 3.77)., Conclusions: In critically ill patients, in Australia and New Zealand, exposure to older RBCs is independently associated with an increased risk of death.

Objective: To describe the relationship between clinical practice and national guidelines for the transfusion of red blood cells (RBCs), fresh frozen plasma (FFP), platelets, and cryoprecipitate in Australian and New Zealand intensive care units (ICUs)., Setting: Forty-seven ICUs over a 5-week period from August to September 2008., Design: Prospective, observational, multicentre, cohort study., Patients: A total of 874 patients receiving any type of blood transfusion., Methods: All patients who were transfused at least one unit of any blood component were included. Patient-specific and blood-component specific data were gathered. Pre-transfusion haemoglobin, platelet count, international normalised ratio (INR), and fibrinogen levels were compared to national guidelines., Results: Of all 874 patients, 757 received RBCs (86.6%), 231 (26.4%) received platelets, 340 (38.9%) received FFP, and 78 (8.9%) received cryoprecipitate. Bleeding was the reason for administration of RBCs in 46%, FFP in 55%, and platelets in 47% of transfusions. The mean (SD) pre-transfusion haemoglobin was 77.6 (9.5) g/l, while the geometric means (95% CI) for platelet count, INR, and fibrinogen were 67.0 (59.7-75.3) x 10(9)/l, 1.84 (1.76-1.93), and 1.4 (1.1-1.8) g/l, respectively. The proportions of transfusions not adherent to guidelines were 2% for RBC, but 53% for platelets, 29% for FFP, and 88% for cryoprecipitate (RBC vs. other transfusion p < 0.001 for all)., Conclusions: Transfusion practice of RBCs in Australian and New Zealand ICUs is restrictive and is concordant with guidelines. However, the transfusion of other blood components is not.

Recombinant factor VIIa (rFVIIa) is used in the treatment of life-threatening haemorrhage that is refractory to conventional treatment. The evidence supporting this practice in patients with liver disease is very limited. It has been used as a salvage therapy in end-stage liver disease (ESLD), in orthotopic liver transplant (OLT), other surgery, and upper gastrointestinal bleeding (UGIB) subpopulations. It has also been used prior to procedures in patients with ESLD. Data were collected by the Australia and New Zealand Haemostasis Registry (ANZHR) to perform a retrospective cohort study on the different subgroups of liver patients. This included 115 cases of use of rFVIIa in liver patients from 20 hospitals. A retrospective cohort study on the different subgroups of liver patients was performed. Main outcome measures were reduction or cessation of bleeding and 28-day mortality. Variables previously shown to predict response to bleeding after administration of rFVIIa were examined to determine whether correlations exist. Salvage therapy with rFVIIa was associated with reduction or cessation in bleeding in 24 of 36 OLT patients, 24 of 36 UGIB patients and 15 of 26 of other surgery patients. Clinical response to rFVIIa in OLT patients and other surgery patients was associated with a significantly lower mortality compared to nonresponders (P = 0.003 and 0.022, respectively). There was no relationship between mortality and bleeding response in patients with UGIB. Variables including acidosis, hypothermia, hypofibrinogenaemia, thrombocytopenia and Model of End-Stage Liver Disease (MELD) score were not associated with clinical response to rFVIIa. Five cases of use prior to procedures are described. Recombinant FVIIa is used as rescue therapy in surgical patients with ESLD and refractory haemorrhage in Australia and New Zealand. Traditional haemostasis variables were not associated with clinical response to rFVIIa in this cohort. Response to rFVIIa is associated with decreased mortality in ESLD patients undergoing OLT and other surgery, but not in UGIB.

Synapsin III is a neuron-specific phosphoprotein that plays an important role in synaptic transmission and neural development. While synapsin III is abundant in embryonic brain, expression of the protein in adults is reduced and limited primarily to the hippocampus, olfactory bulb and cerebral cortex. Given the specificity of synapsin III to these brain areas and because it plays a role in neurogenesis in the dentate gyrus, we investigated whether it may affect learning and memory processes in mice. To address this point, synapsin III knockout mice were examined in a general behavioral screen, several tests to assess learning and memory function, and conditioned fear. Mutant animals displayed no anomalies in sensory and motor function or in anxiety- and depressive-like behaviors. Although mutants showed minor alterations in the Morris water maze, they were deficient in object recognition 24 h and 10 days after training and in social transmission of food preference at 20 min and 24 h. In addition, mutants displayed abnormal responses in contextual and cued fear conditioning when tested 1 or 24 h after conditioning. The synapsin III knockout mice also showed aberrant responses in fear-potentiated startle. As synapsin III protein is decreased in schizophrenic brain and because the mutant mice do not harbor obvious anatomical deficits or neurological disorders, these mutants may represent a unique neurodevelopmental model for dissecting the molecular pathways that are related to certain aspects of schizophrenia and related disorders.

Background: Recombinant activated factor VII (rFVIIa) is increasingly being used off-license for treating critical bleeding. Guidelines may therefore be useful for improving processes and outcomes. Little is known regarding guidelines for off-license rFVIIa or their association with patient outcomes., Objectives: To investigate the availability of hospital guidelines for off-license rFVIIa use and the association between these guidelines and mortality., Methods: Data were extracted from the Haemostasis Registry, which collects all cases of off-license rFVIIa use in participating institutions in Australia and New Zealand. Contributing hospitals were requested to supply a copy of the institutional guideline relating to off-license rFVIIa administration. The characteristics of patients treated in accordance with all elements of the guidelines were compared with those of patients for who one or more guideline elements had been violated. The relationship between guideline-directed treatment and 28-day mortality was investigated using stepwise logistic regression., Results: Two thousand five hundred and fifty-one patients in 75 hospitals were available for analysis. Of these hospitals, 58 provided a guideline for analysis. Patients complying with all guideline elements (n = 530) did not differ from patients receiving care that violated guidelines (n = 1035) regarding age, size of dose, or gender. Guideline-directed treatment was not found to have an association with 28-day mortality following logistic regression., Conclusions: Few patients are treated in accordance with the criteria of rFVIIa guidelines, despite their availability in the majority of hospitals. Moreover, 28-day mortality does not appear to be associated with the use of guidelines in this patient group. Refinement of guidelines relating to the off-license use of rFVIIa is therefore required.

Objective: Through the Australian and New Zealand Haemostasis Registry, we report on the Australian and New Zealand experience with recombinant activated factor VII (rFVIIa) in obstetric patients., Methods: The role of rFVIIa for off-label indications, including trauma, cardiac surgery, and severe postpartum hemorrhage, remains controversial. The Haemostasis Registry established by Monash University in Melbourne, Australia monitors off-label use of rFVIIa across Australia and New Zealand. The purpose of this study was to summarize Registry data for all obstetric hemorrhage patients treated with rFVIIa at participating hospitals between January 2002 and July 2008. The primary outcome measures were reduction or cessation of bleeding (positive therapeutic response), mortality, and hysterectomy rate., Results: During the study period, the Registry received data for 2128 patients. This included 110 cases of administration of rFVIIa in obstetric patients from 38 hospitals, comprising 5% of the total Registry population, 105 of whom were treated for acute hemorrhage. Women received median (interquartile range) individual doses of 92 microg/kg (73-100) of rFVIIa (median total dose 92 microg/kg [58-108]), and 78% of patients received a single dose. The positive response rate to rFVIIa was 76% with 64% responding to the first dose. Ninety-one percent of women were alive at 28 days. Forty-three women (41%) underwent hysterectomy before receiving rFVIIa and, of those remaining, 13 (21%) required hysterectomy after rFVIIa therapy. Two thromboembolic events (1 pulmonary embolism and 1 deep venous thrombosis) and 1 case of hypoxic-ischemic encephalopathy resulting from severe anoxia were reported., Conclusions: The reported effect of rFVIIa in many, but not all, obstetric cases was positive. There was no mortality as a result of thromboembolic complications. Randomized, controlled trials are required to confirm its safety and efficacy and to assess the possibility that use at an earlier stage in treatment of severe postpartum hemorrhage may avoid the need to resort to postpartum hysterectomy for control of bleeding, thus preserving fertility.

Recombinant activated factor VII (rFVIIa), developed and effective in managing inhibitors in haemophilia patients, is being widely used off-label as a "panhaemostatic agent" with ongoing controversy as to its benefits and risks in terms of controlling critical haemorrhage and improving patient outcomes. Current insights into haemostatic mechanisms have resulted in a better understanding of the central role of FVII/FVIIa and tissue factor in the localization and initiation of haemostasis. There is a plethora of case reports and series published on the use of rFVIIa in critical life-threatening haemorrhage and in perioperative settings associated with significant blood loss or the potential for catastrophic haemorrhage. Additionally, the literature is replete with reviews for the use of rFVIIa in various clinical settings, but there is a dearth of good evidence from randomized controlled trials for efficacy. Safety, especially from the thrombogenicity perspective, has been a major issue, but turns out to be less of a concern with thrombotic potential needing to be weighed against the anticipated benefits. Although there is some clinical trial and observational data supporting efficacy it has been difficult to recommend clear clinical practice guidelines, especially as clinical outcome data in terms of morbidity and mortality is limited. Some of the best evidence relates to reduction in allogeneic blood transfusion requirements. This in itself is important and probably clinically relevant in view of the accumulating evidence that allogeneic blood transfusion is an independent risk factor for poorer clinical outcome. It is unlikely that there will be adequate randomized clinical trials to better answer the question of efficacy, thus making data from registries of greater importance. Indeed, the process of establishing efficacy, safety and regulation of a therapeutic that is increasingly used off-label is not without significant difficulties.

G protein-coupled receptor kinase-interactor 2 (GIT2) is a signaling scaffold protein that also functions as GTPase-activating protein (GAPs) for ADP-ribosylation factor (Arf) small GTP-binding proteins. GIT2 has been implicated in the regulation of G protein-coupled receptor trafficking and cell adhesion and migration. To evaluate possible neurobehavioral functions of GIT2 in vivo, we evaluated GIT2-knockout (KO) mice for abnormalities in emotionality and mood. Male and female GIT2-KO mice presented with anxiety-like behaviors in the zero-maze and light-dark emergence tests. Immobility times in tail suspension were reduced in GIT2-KO males, but were normal in GIT2-KO females. Hence, GIT2-KO mice display anxiety-like behavior in an absence of depressive-like responses.

While conventional practice is to discontinue aspirin prior to elective cardiac surgery there is evidence that its continuation may be associated with improved perioperative outcomes. However, uncertainty exists regarding the efficacy of antifibrinolytic agents in the presence of aspirin. We performed a systematic review and meta-analysis of the literature to address the question of the effects of antifibrinolytic agents in cardiac surgery patients maintained on aspirin in terms of both efficacy and adverse events. We conducted an extensive search for randomized controlled trials of antifibrinolytic use in adult patients undergoing coronary artery bypass grafting +/- valve surgery, where aspirin therapy was maintained or initiated through the preoperative period. Data from 17 trials (n=1620) confirmed the efficacy of antifibrinolytic therapy to reduce both chest-tube drainage (weighted mean difference 374 ml, 95% CI 275-473 ml; P<0.00001) and blood transfusion requirements (odds ratio 0.37, 95% CI 0.27-0.49; P<0.00001) in cardiac surgical patients receiving aspirin. We found no difference in the rates of adverse events between groups but observed a trend towards a reduced risk for the composite outcome of thrombotic complications (odds ratio 0.49, 95% CI 0.21-1.13; P=0.09). Antifibrinolytic agents are effective for reducing both chest-tube drainage and transfusion requirements in cardiac surgical patients receiving aspirin. We found no difference between antifibrinolytic and placebo in terms of adverse events but the population was predominantly low-risk. Further studies are required to determine the optimal balance between antiplatelet and antifibrinolytic effects in cardiac surgery.

P311 is an 8-kDa protein that is expressed in many brain regions, particularly the hippocampus, cerebellum and olfactory lobes, and is under stringent regulation by developmental, mitogenic and other physiological stimuli. P311 is thought to be involved in the transformation and motility of neural cells; however, its role in normal brain physiology is undefined. To address this point, P311-deficient mice were developed through gene targeting and their behaviors were characterized. Mutants displayed no overt abnormalities, bred normally and had normal survival rates. Additionally, no deficiencies were noted in motor co-ordination, balance, hearing or olfactory discrimination. Nevertheless, P311-deficient mice showed altered behavioral responses in learning and memory. These included impaired responses in social transmission of food preference, Morris water maze and contextual fear conditioning. Additionally, mutants displayed altered emotional responses as indicated by decreased freezing in contextual and cued fear conditioning and reduced fear-potentiated startle. Together, these data establish P311 as playing an important role in learning and memory processes and emotional responses.